An increasing body of evidence indicated that pancreatic beta cell dysfunction is of central importance in the pathogenesis of spontaneous diabetes. Although insulin deficiency and a decrease in islet and beta cell mass are findings of major pathologic significance in this disease, the precise mechanisms responsible for these changes are poorly understood. These abnormalities may be the result of one or more defects involving beta cell neogenesis, insulin biosynthesis or insulin release. The overall objective of this project is to obtain an integrated view of the physiology, biochemistry and morphology of the pancreatic islets with specific emphasis on mechanisms controlling beta cell replication and insulin biosynthesis, storage and release. The methods to be employed will rely primarily on applying monolayer cell culture techniques to study mammalian beta cells from a variety of sources; recently developed morphologically differentiated transplantable beta cell tumors with high insulin content will also be utilized in order to facilitate studies in which limitation of starting material has previously posed a major obstacle. An additional objective will be to utilize the technology for growth and maintenance of beta cells in tissue culture to develop an artificial implantable endocrine pancreas containing living beta cells.